Abstract:

A pyrimidone derivative represented by formula (I) or a salt thereof, or a
solvate thereof or a hydrate thereof:
##STR00001##
Wherein Y, Z, R1, R2, R3, R4, R5, R6, R7, n, m, and o are as described
herein. The invention relates also to a medicament comprising the said
derivative or a salt thereof as an active ingredient which is used for
preventive and/or therapeutic treatment of a neurodegenerative disease
caused by abnormal activity of GSK3β, such as Alzheimer disease.

Claims:

1. A compound of formula (I) or a salt, a solvate or a hydrate thereof:
##STR00191## wherein:Y represents two hydrogen atoms, a sulfur atom, an
oxygen atom or a C1-2 alkyl group and a hydrogen atom;Z represents a
bond, an oxygen atom, a nitrogen atom substituted by a hydrogen atom or a
C1-3 alkyl group, a sulfur atom, a methylene group optionally
substituted by one or two groups chosen from a C1-6 alkyl group, a
hydroxyl group, a C1-6 alkoxy group, a C1-2 perhalogenated
alkyl group or an amino group;R1 represents a 2, 3 or 4-pyridine ring or
a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted by a
C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom;R2
represents a benzene ring or a naphthalene ring; the rings being
optionally substituted by 1 to 4 substituents selected from a C1-6
alkyl group, C3-7 cycloalkyl group, a C3-7 cycloalkyl-C1-6
alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a
C1-3 halogenated alkyl group, a hydroxyl group, a C1-6 alkoxy
group optionally substituted by a C3-5 cycloalkyl group, a C1-2
perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a
cyano, an amino, a C1-6 monoalkylamino group, a C2-12
dialkylamino group, an acetoxy group or an aminosulfonyl group;R3
represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;R4
represents a hydrogen atom or a C1-6 alkyl group;R5 represents a
hydrogen atom, a C1-6 alkyl group optionally substituted by 1 to 4
substituents selected from a halogen atom, a phenyl group, a hydroxyl
group or a C1-6 alkoxy group;R6 represents a hydrogen atom, a
C1-6 alkyl group or a halogen atom;R7 represents a hydrogen atom or
a C1-6 alkyl group; andn represents 0 to 3; m represents 0 to 1; o
represents 0 to 2.

2. The compound or a salt, a solvate or a hydrate thereof according to
claim 1, wherein R1 represents an unsubstituted 4-pyridine ring or
unsubstituted 4-pyrimidine ring.

3. The compound or a salt, a solvate or a hydrate thereof according to
claim 1, wherein:R1 represents a 3- or 4-pyridine ring or alternatively a
4- or 5-pyrimidine ring; the rings being optionally substituted by a
C1-2 alkyl group, a C1-2 alkoxy group or a halogen atom;R2
represents a benzene ring or a naphthalene ring; the rings being
optionally substituted by 1 to 4 substituents selected from a C1-3
alkyl group, C3-5 cycloalkyl group, a C3-5 cycloalkyl-C1-4
alkyl group, a halogen atom, a C1-3 halogenated alkyl group, a
hydroxyl group, a C1-3 alkoxy group optionally substituted by a
C3-5 cycloalkyl group, a C1-2 perhalogenated alkoxy group, a
C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-3
monoalkylamino group or a C2-6 dialkylamino group;R3 represents a
hydrogen atom, a C1-3 alkyl group or a halogen atom;R4 represents a
hydrogen atom or a C1-3 alkyl group;R5 represents a hydrogen atom, a
C1-3 alkoxy carbonyl group or a C1-3 alkyl group optionally
substituted by 1 to 4 substituents selected from a halogen atom, a phenyl
group, a hydroxyl group or a C1-3 alkoxy group;R6 represents a
hydrogen atom, a C1-3 alkyl group or a halogen atom;R7 represents a
hydrogen atom or a C1-3 alkyl group;Y represents two hydrogen atoms,
an oxygen atom or a C1-2 alkyl group and a hydrogen atom;Z
represents a bond, an oxygen atom, a nitrogen atom substituted by a
hydrogen atom or a C1-3 alkyl group, a methylene group optionally
substituted by one or two groups chosen from a C1-3 alkyl group, a
hydroxyl group, a C1-3 alkoxy group, a C1-2 perhalogenated
alkyl group or an amino group;n represents 0 to 3; m represents 0 or 1
and o represents 1 to 2.

4. The compound or a salt, a solvate or a hydrate thereof according to
claim 1, wherein:R1 represents an unsubstituted 4-pyridine ring or
4-pyrimidine ring;R2 represents a benzene ring or a naphthalene ring; the
rings being optionally substituted by 1 to 4 substituents selected from a
C1-3 alkyl group, a C1-2 perhalogenated alkyl group, a
C3-4 cycloalkyl group, a C3-4 cycloalkyl-C1-3 alkyl group,
a halogen atom, a hydroxyl group, a nitro, a cyano, an amino, a C1-3
alkoxy group optionally substituted by a C3-4 cycloalkyl group, a
C1-2 perhalogenated alkoxy group or a C1-3 alkylsulfonyl
group;R3 represents a hydrogen atom or a halogen atom;R4 represents a
hydrogen atom;R5 represents a hydrogen atom;R6 represents a hydrogen atom
or a C1-6 alkyl group;R7 represents a hydrogen atom;Y represents two
hydrogen atoms, or an oxygen atom;Z represents a bond, an oxygen atom, a
nitrogen atom substituted by a hydrogen atom;n represents 0 to 1;m
represents 0 to 1 and o represents 1 to 2.

5. A compound of formula (III): ##STR00192## wherein:m represents 0 or 1;
o represents 0 to 2.R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or
5-pyrimidine ring, the ring being optionally substituted by a C1-6
alkyl group, a C1-6 alkoxy group or a halogen atom;R3 represents a
hydrogen atom, a C1-6 alkyl group or a halogen atom;R4 represents a
hydrogen atom or a C1-6 alkyl group;R5 represents a hydrogen atom, a
C1-6 alkyl group optionally substituted by 1 to 4 substituents
selected from a halogen atom, a phenyl group, a hydroxyl group or a
C1-6 alkoxy group;R6 represents a hydrogen atom, a C1-6 alkyl
group or a halogen atom; andR7 represents a hydrogen atom or a C1-6
alkyl group.

7. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 1 in combination with at least one
pharmaceutically acceptable excipient.

8. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 2 in combination with at least one
pharmaceutically acceptable excipient.

9. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 3 in combination with at least one
pharmaceutically acceptable excipient.

10. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 4 in combination with at least one
pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 5 in combination with at least one
pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 6 in combination with at least one
pharmaceutically acceptable excipient.

13. A method for the treatment of a disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease, taupathies,
non-insulin dependent diabetes, obesity, manic depressive illness and
schizophrenia, which comprises administering to a patient in need of said
treatment a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 1.

14. A method for the treatment of a disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease, taupathies,
non-insulin dependent diabetes, obesity, manic depressive illness and
schizophrenia, which comprises administering to a patient in need of said
treatment a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 2.

15. A method for the treatment of a disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease, taupathies,
non-insulin dependent diabetes, obesity, manic depressive illness and
schizophrenia, which comprises administering to a patient in need of said
treatment a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 3.

16. A method for the treatment of a disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease, taupathies,
non-insulin dependent diabetes, obesity, manic depressive illness and
schizophrenia, which comprises administering to a patient in need of said
treatment a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 4.

17. A method for the treatment of a disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease, taupathies,
non-insulin dependent diabetes, obesity, manic depressive illness and
schizophrenia, which comprises administering to a patient in need of said
treatment a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 5.

18. A method for the treatment of a disease selected from the group
consisting of Alzheimer's disease, Parkinson's disease, taupathies,
non-insulin dependent diabetes, obesity, manic depressive illness and
schizophrenia, which comprises administering to a patient in need of said
treatment a therapeutically effective amount of a compound of formula (I)
or a pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 6.

19. A method of inhibiting the activity of glycogen synthase kinase 3-beta
(GSK3-.beta.), which comprises administering to a patient in need of said
inhibition an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 1.

20. A method of inhibiting the activity of glycogen synthase kinase 3-beta
(GSK3-.beta.), which comprises administering to a patient in need of said
inhibition an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 2.

21. A method of inhibiting the activity of glycogen synthase kinase 3-beta
(GSK3-.beta.), which comprises administering to a patient in need of said
inhibition an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 3.

22. A method of inhibiting the activity of glycogen synthase kinase 3-beta
(GSK3-.beta.), which comprises administering to a patient in need of said
inhibition an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 4.

23. A method of inhibiting the activity of glycogen synthase kinase 3-beta
(GSK3-.beta.), which comprises administering to a patient in need of said
inhibition an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 5.

24. A method of inhibiting the activity of glycogen synthase kinase 3-beta
(GSK3-.beta.), which comprises administering to a patient in need of said
inhibition an effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, or a solvate or a hydrate
thereof according to claim 6.

Description:

CROSS REFERENCE TO RELATED APPLICATIONS

[0001]This application is a continuation of International application No.
PCT/IB2006/004,046, filed Nov. 21, 2006, which is incorporated herein by
reference in its entirety; which claims the benefit of priority of
European Patent Application No. 05292457.8, filed Nov. 21, 2005.

BACKGROUND OF THE INVENTION

[0002]1. Field of the Invention

[0003]The present invention relates to compounds that are useful as an
active ingredient of a medicament for preventive and/or therapeutic
treatment of neurodegenerative diseases caused by abnormal activity of
GSK3β.

[0004]2. Background Art

[0005]GSK3β (glycogen synthase kinase 3β) is a proline directed
serine, threonine kinase that plays an important role in the control of
metabolism, differentiation and survival. It was initially identified as
an enzyme able to phosphorylate and hence inhibit glycogen synthase. It
was later recognized that GSK3β was identical to tau protein kinase
1 (TPK1), an enzyme that phosphorylates tau protein in epitopes that are
also found to be hyperphosphorylated in Alzheimer's disease and in
several taupathies.

[0006]Interestingly, protein kinase B (AKT) phosphorylation of GSK3β
results in a loss of its kinase activity, and it has been hypothesized
that this inhibition may mediate some of the effects of neurotrophic
factors. Moreover, phosphorylation by GSK3β of β-catenin, a
protein involved in cell survival, results in its degradation by an
ubiquitinilation dependent proteasome pathway.

[0007]Thus, it appears that inhibition of GSK3β activity may result
in neurotrophic activity. Indeed there is evidence that lithium, an
uncompetitive inhibitor of GSK3β, enhances neuritogenesis in some
models and also increases neuronal survival, through the induction of
survival factors such as Bcl-2 and the inhibition of the expression of
proapoptotic factors such as P53 and Bax.

[0008]Recent studies have demonstrated that β-amyloid increases the
GSK3β activity and tau protein phosphorylation. Moreover, this
hyperphosphorylation as well as the neurotoxic effects of β-amyloid
are blocked by lithium chloride and by a GSK3β antisense mRNA. These
observations strongly suggest that GSK3β may be the link between the
two major pathological processes in Alzheimer's disease: abnormal APP
(Amyloid Precursor Protein) processing and tau protein
hyperphosphorylation.

[0009]Although tau hyperphosphorylation results in a destabilization of
the neuronal cytoskeleton, the pathological consequences of abnormal
GSK3β activity are, most likely, not only due to a pathological
phosphorylation of tau protein because, as mentioned above, an excessive
activity of this kinase may affect survival through the modulation of the
expression of apoptotic and antiapoptotic factors. Moreover, it has been
shown that β-amyloid-induced increase in GSK3β activity results
in the phosphorylation and, hence the inhibition of pyruvate
dehydrogenase, a pivotal enzyme in energy production and acetylcholine
synthesis.

[0010]Altogether these experimental observations indicate that GSK3β
may find application in the treatment of the neuropathological
consequences and the cognitive and attention deficits associated with
Alzheimer's disease, as well as other acute and chronic neurodegenerative
diseases and other pathologies where GSK3β is deregulated (Nature
reviews Vol. 3, June 2004, p. 479-487; Trends in Pharmacological Sciences
Vol. 25 No. 9, September 2004, p. 471-480; Journal of neurochemistry
2004, 89, 1313-1317; Medicinal Research Reviews, Vol. 22, No. 4, 373-384,
2002).

[0012]Inhibitors of GSK3β may also find application in the treatment
of other nervous system disorders, such as bipolar disorders
(manic-depressive illness). For example lithium has been used for more
than 50 years as a mood stabilizer and the primary treatment for bipolar
disorder. The therapeutic actions of lithium are observed at doses (1-2
mM) where it is a direct inhibitor of GSK3β. Although the mechanism
of action of lithium is unclear, inhibitors of GSK3β could be used
to mimic the mood stabilizing effects of lithium. Alterations in
Akt-GSK3β signaling have also been implicated in the pathogenesis of
schizophrenia.

[0013]In addition, inhibition of GSK3β could be useful in treating
cancers, such as colorectal, prostate, breast, non-small lung carcinoma,
thyroid cancer, T or B-cell leukemia and several virus-induced tumors.
For example, the active form of GSK3β has been shown to be elevated
in the tumors of colorectal cancer patients and inhibition of GSK3β
in colorectal cancer cells activates p53-dependent apoptosis and
antagonizes tumor growth. Inhibition of GSK3β also enhances
TRAIL-induced apoptosis in prostate cancer cell lines. GSK3β also
plays a role in the dynamics of the mitototic spindle and inhibitors of
GSK3β prevent chromosome movement and lead to a stabilization of
microtubules and a prometaphase-like arrest that is similar to that
observed with low doses of Taxol. Other possible applications for
GSK3β inhibitors include therapy for non-insulin dependent diabetes
(such as diabetes type II), obesity and alopecia.

[0014]Recently, both human genetics and animal studies have pointed out
the role of Wnt/LPR5 pathway as a major regulator of bone mass accrual.
Inhibition of GSK3β leads to the consequent activation of canonical
Wnt signaling. Because deficient Wnt signaling has been implicated in
disorders of reduced bone mass, GSK3β inhibitors may also be used
for treating disorders of reduced bone mass, bone-related pathologies,
osteoporosis.

[0015]Inhibitors of human GSK3β may also inhibit pfGSK3, an ortholog
of this enzyme found in Plasmodium falciparum, as a consequence they
could be used for the treatment of malaria (Biochimica et Biophysica Acta
1697, 181-196, 2004).

[0016]According to recent data, GSK3beta inhibitors might be used in the
treatment or prevention Pemphigus vulgaris.

[0017]According to recent studies, show that GSK3beta inhibitor treatment
improved neutrophil and megakaryocyte recovery. Therefore, GSK3beta
inhibitors will be useful for the treatment of neutropenia induced by
cancer chemotherapy.

SUMMARY OF THE INVENTION

[0018]An object of the present invention is to provide compounds useful as
an active ingredient of a medicament for preventive and/or therapeutic
treatment of a disease caused by abnormal GSK3β activity, more
particularly of neurodegenerative diseases. More specifically, the object
is to provide novel compounds useful as an active ingredient of a
medicament that enables prevention and/or treatment of neurodegenerative
diseases such as Alzheimer's disease.

[0019]Thus, the inventors of the present invention have identified
compounds possessing inhibitory activity against GSK3β. As a result,
they found that compounds represented by the following formula (I) had
the desired activity and were useful as an active ingredient of a
medicament for preventive and/or therapeutic treatment of the
aforementioned diseases.

[0020]The present invention thus provides as an object of the invention
the pyrimidone derivatives represented by formula (I) or salts thereof,
solvates thereof or hydrates thereof:

##STR00002##

wherein:Y represents two hydrogen atoms, a sulfur atom, an oxygen atom or
a C1-2 alkyl group and a hydrogen atom;Z represents a bond, an
oxygen atom, a nitrogen atom substituted by a hydrogen atom or a
C1-3 alkyl group, a sulfur atom, a methylene group optionally
substituted by one or two groups chosen from a C1-6 alkyl group, a
hydroxyl group, a C1-6 alkoxy group, a C1-2 perhalogenated
alkyl group or an amino group;R1 represents a 2, 3 or 4-pyridine ring or
a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted by a
C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom;R2
represents a benzene ring or a naphthalene ring; the rings being
optionally substituted by 1 to 4 substituents selected from a C1-6
alkyl group, C3-7 cycloalkyl group, a C3-7 cycloalkyl-C1-6
alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a
C1-3 halogenated alkyl group, a hydroxyl group, a C1-6alkoxy
group optionally substituted by a C3-5 cycloalkyl group, a C1-2
perhalogenated alkoxy group, a C1-6 alkylsulfonyl group, a nitro, a
cyano, an amino, a C1-6 monoalkylamino group or a C2-12
dialkylamino group, an acetoxy group or an aminosulfonyl group;R3
represents a hydrogen atom, a C1-6 alkyl group or a halogen atom;R4
represents a hydrogen atom or a C1-6 alkyl group;R5 represents a
hydrogen atom, a C1-6 alkyl group optionally substituted by 1 to 4
substituents selected from a halogen atom, a phenyl group, a hydroxyl
group or a C1-6 alkoxy group;R6 represents a hydrogen atom, a
C1-6 alkyl group or a halogen atom;R7 represents a hydrogen atom or
a C1-6 alkyl group; andn represents 0 to 3; m represents 0 to 1; o
represents 0 to 2.

[0021]According to another aspect of the present invention, there is
provided a medicament comprising as an active ingredient a substance
selected from the group consisting of the pyrimidone derivatives
represented by formula (I) and the physiologically acceptable salts
thereof, and the solvates thereof and the hydrates thereof. As preferred
embodiments of the medicament, there are provided the aforementioned
medicament which is used for preventive and/or therapeutic treatment of
diseases caused by abnormal GSK3β activity, and the aforementioned
medicament which is used for preventive and/or therapeutic treatment of
neurodegenerative diseases and in addition other diseases such as:
Non-insulin dependent diabetes (such as diabetes type II) and obesity;
malaria, bipolar disorders (manic depressive illness); schizophrenia;
alopecia or cancers such as colorectal, prostate, breast cancer,
non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia,
several virus-induced tumors and bone related pathologies. The medicament
could also find an application in regenerative medicine.

DETAILED DESCRIPTION OF THE INVENTION

[0022]As further embodiments of the present invention, there are provided
the aforementioned medicament wherein the diseases are neurodegenerative
diseases and are selected from the group consisting of Alzheimer's
disease, Parkinson's disease, taupathies (e.g. Fronto temporal dementia,
corticobasal degeneration, Pick's disease, progressive supranuclear
palsy), Wilson's disease, Huntington's disease, Prion disease and other
dementia including vascular dementia; acute stroke and others traumatic
injuries; cerebrovascular accidents (e.g. age related macular
degeneration); brain and spinal cord trauma; amyotrophic lateral
sclerosis; peripheral neuropathies; retinopathies and glaucoma, and the
aforementioned medicament in the form of pharmaceutical composition
containing the above substance as an active ingredient together with one
or more pharmaceutical additives.

[0023]As further embodiments of the present invention, there are provided
the aforementioned medicament wherein the bones related pathologies are
osteoporosis.

[0024]The present invention further provides an inhibitor of GSK3β
activity comprising as an active ingredient a substance selected from the
group consisting of the pyrimidone derivatives of formula (I) and the
salts thereof, and the solvates thereof and the hydrates thereof.

[0025]According to further aspects of the present invention, there is
provided a method for preventive and/or therapeutic treatment of
neurodegenerative diseases caused by abnormal GSK3β activity, which
comprises the step of administering to a patient a preventively and/or
therapeutically effective amount of a substance selected from the group
consisting of pyrimidone derivatives of formula (I) and the
physiologically acceptable salts thereof, and the solvates thereof and
the hydrates thereof; and a use of a substance selected from the group
consisting of the pyrimidone derivatives of formula (I) and the
physiologically acceptable salts thereof, and the solvates thereof and
the hydrates thereof for the manufacture of the aforementioned
medicament.

[0032]The C2-12 dialkylamino group represents an amino group
substituted by two C1-6 alkyl groups, for example, dimethylamino
group, ethylmethylamino group, diethylamino group, methylpropylamino
group and diisopropylamino group and the like;

[0033]A leaving group L represents a group which could be easily cleaved
and substituted, such a group may be for example a tosyl, a mesyl, a
bromide and the like.

[0034]The compounds represented by the aforementioned formula (I) may form
a salt. Examples of the salt include, when an acidic group exists, salts
of alkali metals and alkaline earth metals such as lithium, sodium,
potassium, magnesium, and calcium; salts of ammonia and amines such as
methylamine, dimethylamine, trimethylamine, dicyclohexylamine,
tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,
2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and
L-glucamine; or salts with basic amino acids such as lysine,
δ-hydroxylysine and arginine. The base-addition salts of acidic
compounds are prepared by standard procedures well known in the art.

[0036]The acid-addition salts of the basic compounds are prepared by
standard procedures well know in the art which include, but are not
limited thereto, dissolving the free base in an aqueous alcohol solution
containing the appropriate acid and isolating the salt by evaporating the
solution, or by reacting the free base and an acid in an organic solvent,
in which case the salt separates directly, or is precipitated with a
second organic solvent, or can be obtained by concentration of the
solution. The acids which can be used to prepare the acid-addition salts
include preferably those which produce, when combined with the free base,
pharmaceutically-acceptable salts, that is, salts whose anions are
relatively innocuous to the animal organism in pharmaceutical doses of
the salts, so that the beneficial properties inherent in the free base
are not compromised by side effects ascribable to the anions. Although
medicinally acceptable salts of the basic compounds are preferred, all
acid-addition salts are within the scope of the present invention.

[0037]In addition to the pyrimidone derivatives represented by the
aforementioned formula (I) and salts thereof, their solvates and hydrates
also fall within the scope of the present invention.

[0038]The pyrimidone derivatives represented by the aforementioned formula
(I) may have one or more asymmetric carbon atoms. As for the
stereochemistry of such asymmetric carbon atoms, they may independently
be in either (R) and (S) configuration, and the derivative may exist as
stereoisomers such as optical isomers, or diastereoisomers. Any
stereoisomers in pure form, any mixtures of stereoisomers, racemates and
the like fall within the scope of the present invention.

[0039]Examples of compounds of the present invention are shown in table 1
hereinafter. However, the scope of the present invention is not limited
by these compounds.

[0040]An object of the present invention includes also compounds
represented by formula (I) wherein m, n, o are as defined above and:

(1) R1 represents a 3- or 4-pyridine ring alternatively a 4- or
5-pyrimidine ring; the ring being optionally substituted by a C1-2
alkyl group, a C1-2 alkoxy group or a halogen atom; and/or(2) R2
represents a benzene ring or a naphthalene ring; the rings being
optionally substituted by 1 to 4 substituents selected from a C1-3
alkyl group, C3-5 cycloalkyl group, a C3-5 cycloalkyl-C1-4
alkyl group, a halogen atom, a C1-2 perhalogenated alkyl group, a
hydroxyl group, a C1-3 alkoxy group optionally substituted by a
C3-5 cycloalkyl group, a C1-2 perhalogenated alkoxy group, a
C1-6 alkylsulfonyl group, a nitro, a cyano, an amino, a C1-3
monoalkylamino group or a C2-6 dialkylamino group; and/or(3) R3
represents a hydrogen atom, a C1-3 alkyl group or a halogen atom;(4)
R4 represents a hydrogen atom or a C1-3 alkyl group; and/or(5) R5
represents a hydrogen atom, a C1-3 alkoxy carbonyl group or a
C1-3 alkyl group optionally substituted by 1 to 4 substituents
selected from a halogen atom, a phenyl group, a hydroxyl group or a
C1-3 alkoxy group; and/or(6) R6 represents a hydrogen atom, a
C1-3 alkyl group or a halogen atom; and/or(7) R7 represents a
hydrogen atom or a C1-3 alkyl group; and/or(8) Y represents two
hydrogen atoms, an oxygen atom or a C1-2 alkyl group and a hydrogen
atom; and/or(9) Z represents a bond, an oxygen atom, a nitrogen atom
substituted by a hydrogen atom or a C1-3 alkyl group, a methylene
group optionally substituted by one or two groups chosen from a C1-3
alkyl group, a hydroxyl group, a C1-3 alkoxy group, a C1-2
perhalogenated alkyl group or an amino group; and/or(10) n represents 0
to 3;(11) m represents 0 to 1; o represents 1 to 2; and more particularly
wherein R1, R2, R3, R4, R5, R6, R7, m, n, o, Y and Z are as defined
here-above.

[0041]Another object of the present invention includes compounds
represented by formula (I) wherein m, n and o are as defined above and:

[0043](2) R2 represents a benzene ring or a naphthalene; the ring being
optionally substituted by 1 to 4 substituents selected from a C1-3
alkyl group, a C1-2 perhalogenated alkyl group, a C3-4
cycloalkyl group, a C3-4 cycloalkyl-C1-3 alkyl group, a halogen
atom, a hydroxyl group, a nitro, a cyano, an amino, a C1-3 alkoxy
group optionally substituted by a C3-4 cycloalkyl group, a C1-2
perhalogenated alkoxy group or a C1-3 alkylsulfonyl group; and/or

[0149]As a further object, the present invention concerns also methods for
preparing the pyrimidone compounds represented by the aforementioned
formula (I).

[0150]These compounds can be prepared, for example, according to methods
explained below.

Preparation Method

[0151]Pyrimidone compounds represented by the aforementioned formula (I),
may be prepared according to the method described in the scheme 1.

##STR00003##

[0152](In the above scheme the definition of R1, R2, R3, R4, R5, R6, R7,
m, n, o, Y and Z are the same as those already described for compound of
formula (I)).

[0153]Following this method, the pyrimidone derivative represented by the
above formula (III), wherein R1, R3, R4, R5, R6, R7, m and o are as
defined for compound of formula (I), is allowed to react with a base such
as triethylamine, sodium carbonate or potassium carbonate in a solvent
such as tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylacetamide or
chloroform at a suitable temperature ranging from 0 to 130° C.
under ordinary air, then with a compound of formula (II), wherein R2, Z,
Y and n are as defined for compound of formula (I) and L represents a
leaving group preferably chlorine, bromide or mesyl group, to obtain the
compound of the aforementioned formula (I).

[0154]Alternatively compounds of formula (I) wherein Y represents two
hydrogen atoms may be prepared by reductive amination of a compound of
formula (II) wherein Y represents an oxygen atom and L represents a
hydrogen atom, by a compound of formula (III) wherein R1, R3, R4, R5, R6,
m and o are as defined for compound of formula (I) and R7 is a hydrogen,
according to well known methods to one skilled in the art.

[0155]Compound of formula (II) is commercially available or may be
synthesized according to well-known methods to one skilled in the art.

[0156]Compound of formula (III) may be prepared according to the method
defined in scheme 2.

##STR00004##

(In the above scheme the definition of R1, R2, R3, R4, R5, R6, m and o are
the same as already described.)

[0157]According to this method, the 3-ketoester of formula (IV), wherein
R1 and R3 are as defined for compound of formula (I), R is an alkyl group
such as for example methyl or ethyl, is allowed to react with a compound
of formula (V) wherein R4, R5, R6, m and o are as defined for compound of
formula (I) and Pg is a suitable protecting group such as for example a
phthalimido group. The reaction may be carried out in the presence of a
base such as potassium carbonate, in an alcoholic solvent such as
methanol, ethanol and the like or without, at a suitable temperature
ranging from 25° to 140° C. under ordinary air.

[0158]Additionally compound of formula (III) wherein R3 represents a
hydrogen atom may be halogenated in order to give compounds of formula
(III) wherein R3 is a halogen atom such as a bromine atom or a chlorine
atom. The reaction may be carried out in an acidic medium such as acetic
acid or propionic acid, in presence of bromosuccinimide or
chlorosuccinimide, or bromine.

[0160]In addition, compounds of formula (IV) wherein R3 represents a
hydrogen atom may be obtained by analogy to the method described in
patent DE 2705582.

[0161]As a further object, the present invention concerns also the
compounds of formula (III) as intermediates of compounds of formula (I).

[0162]Compound of formula (IV) is commercially available or may be
synthesized according to well-known methods to one skilled in the art.

[0163]For example compounds of formula (IV), wherein R1 represent a
pyridine ring or a pyrimidine ring, optionally substituted by a
C1-16 alkyl group, C1-6 alkoxy group or a halogen atom, can be
prepared by reacting respectively an isonicotinic acid or a
pyrimidine-carboxylic acid, optionally substituted by a C1-6 alkyl
group, C1-6 alkoxy group or a halogen, with the corresponding
malonic acid monoester. The reaction can be carried out using methods
well known to one skilled in the art, such as for example in presence of
a coupling agent such as 1,1'-carbonylbis-1H-imidazole in a solvent such
as tetrahydrofuran at a temperature ranging from 20 to 70° C.

[0164]Compound of formula (V) may be synthesized according to well-known
methods of one skilled in the art.

[0165]For example compound of formula (V), wherein m, o, R4, R5 and R6 are
as defined for compound of formula (I) and a suitable protecting group Pg
such as for example a phthalimido group, may be prepared according to the
method defined in scheme 3, starting from compound of formula (VI). The
conditions which may be used are given in the chemical examples.

[0167]Compound of formula (VII) and formula (V) may be synthesized
according to the method described in WO96/14844.

[0168]In the above reactions protection or deprotection of a functional
group may sometimes be necessary. A suitable protecting group Pg can be
chosen depending on the type of the functional group, and a method
described in the literature may be applied. Examples of protecting
groups, of protection and deprotection methods are given for example in
Protective groups in Organic Synthesis Greene et al., 3rd Ed. (John Wiley
& Sons, Inc., New York) 1999.

[0169]The compounds of the present invention have inhibitory activity
against GSK3β. Accordingly, the compounds of the present invention
are useful as an active ingredient for the preparation of a medicament,
which enables preventive and/or therapeutic treatment of a disease caused
by abnormal GSK3β activity and more particularly of
neurodegenerative diseases such as Alzheimer's disease. In addition, the
compounds of the present invention are also useful as an active
ingredient for the preparation of a medicament for preventive and/or
therapeutic treatment of neurodegenerative diseases such as Parkinson's
disease, taupathies (e.g. Fronto temporal dementia, corticobasal
degeneration, Pick's disease, progressive supranuclear palsy), Wilson's
disease, Huntington's disease, Prion disease and other dementia including
vascular dementia; acute stroke and others traumatic injuries;
cerebrovascular accidents (e.g. age related macular degeneration); brain
and spinal cord trauma; amyotrophic lateral sclerosis, peripheral
neuropathies; retinopathies and glaucoma; and other diseases such as
non-insulin dependent diabetes (such as diabetes type II) and obesity;
malaria, manic depressive illness; schizophrenia; alopecia; cancers such
as colorectal, prostate breast cancer, non-small cell lung carcinoma,
thyroid cancer, T or B-cell leukemia, several virus-induced tumors and in
bone related pathologies. The medicament could also find an application
in regenerative medicine

[0170]The present invention further relates to a method for treating
neurodegenerative diseases caused by abnormal activity of GSK3β and
of the aforementioned diseases which comprises administering to a
mammalian organism in need thereof an effective amount of a compound of
the formula (I).

[0171]As the active ingredient of the medicament of the present invention,
a substance may be used which is selected from the group consisting of
the compound represented by the aforementioned formula (I) and
pharmacologically acceptable salts thereof, and solvates thereof and
hydrates thereof. The substance, per se, may be administered as the
medicament of the present invention, however, it is desirable to
administer the medicament in a form of a pharmaceutical composition which
comprises the aforementioned substance as an active ingredient and one or
more pharmaceutical additives. As the active ingredient of the medicament
of the present invention, two or more of the aforementioned substances
may be used in combination. The above pharmaceutical composition may be
supplemented with an active ingredient of another medicament for the
treatment of the above mentioned diseases. The type of pharmaceutical
composition is not particularly limited, and the composition may be
provided as any formulation for oral or parenteral administration. For
example, the pharmaceutical composition may be formulated, for example,
in the form of pharmaceutical compositions for oral administration such
as granules, fine granules, powders, hard capsules, soft capsules,
syrups, emulsions, suspensions, solutions and the like, or in the form of
pharmaceutical compositions for parenteral administrations such as
injections for intravenous, intramuscular, or subcutaneous
administration, drip infusions, transdermal preparations, transmucosal
preparations, nasal drops, inhalants, suppositories and the like.
Injections or drip infusions may be prepared as powdery preparations such
as in the form of lyophilized preparations, and may be used by dissolving
just before use in an appropriate aqueous medium such as physiological
saline. Sustained-release preparations such as those coated with a
polymer may be directly administered intracerebrally.

[0172]Types of pharmaceutical additives used for the manufacture of the
pharmaceutical composition, content ratios of the pharmaceutical
additives relative to the active ingredient, and methods for preparing
the pharmaceutical composition may be appropriately chosen by those
skilled in the art. Inorganic or organic substances, or solid or liquid
substances may be used as pharmaceutical additives. Generally, the
pharmaceutical additives may be incorporated in a ratio ranging from 1%
by weight to 90% by weight based on the weight of an active ingredient.

[0173]Examples of excipients used for the preparation of solid
pharmaceutical compositions include, for example, lactose, sucrose,
starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like.
For the preparation of liquid compositions for oral administration, a
conventional inert diluent such as water or a vegetable oil may be used.
The liquid composition may contain, in addition to the inert diluent,
auxiliaries such as moistening agents, suspension aids, sweeteners,
aromatics, colorants, and preservatives. The liquid composition may be
filled in capsules made of an absorbable material such as gelatin.
Examples of solvents or suspension mediums used for the preparation of
compositions for parenteral administration, e.g. injections,
suppositories, include water, propylene glycol, polyethylene glycol,
benzyl alcohol, ethyl oleate, lecithin and the like. Examples of base
materials used for suppositories include, for example, cacao butter,
emulsified cacao butter, lauric lipid, witepsol.

[0174]The dose and frequency of administration of the medicament of the
present invention are not particularly limited, and they may be
appropriately chosen depending on conditions such as a purpose of
preventive and/or therapeutic treatment, a type of a disease, the body
weight or age of a patient, severity of a disease and the like.
Generally, a daily dose for oral administration to an adult may be 0.01
to 1,000 mg (the weight of an active ingredient), and the dose may be
administered once a day or several times a day as divided portions, or
once in several days. When the medicament is used as an injection,
administrations may preferably be performed continuously or
intermittently in a daily dose of 0.001 to 100 mg (the weight of an
active ingredient) to an adult.

[0175]To a solution of 13.474 g (91.1 mmol) of trimethyloxonium
tetrafluoroborate in 294 mL of anhydrous dichloromethane was added 22.25
g (91.1 mmol) of (+/-)-3-phtalimidopiperidin-2-one (Heterocycles (1996),
42(2), 537-42, Enantiomer (2001), 6(5), 275-279, Synthesis (1991), (5),
417-20) and the resulting mixture was stirred at room temperature for 12
h. The mixture was hydrolyzed with a saturated aqueous solution of sodium
hydrogen carbonate, extracted with dichloromethane, dried over sodium
sulfate and the solvent was evaporated to afford 23.22 g (99%) of pure
product as a yellow oil. The compound was used as such in the next step.

[0178]To a solution of 23.224 g (89.92 mmol) of
(+/-)2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-di-
one dissolved in 409 mL of methanol was added at room temperature 4.81 g
(89.92 mmol) of ammonium chloride. The resulting mixture was stirred
under reflux for 12 h. The cooled solution was evaporated to remove
solvent. The residue was triturated with diethyl ether and filtered to
afford 23.8 g (95%) of the pure product as a white powder.

[0182]To a suspension of 9.166 g (32.77 mmol) of (+/-)
2-(2-Amino-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione
hydrochloride (1:1) in 50 mL of toluene was added sodium methanolate
(freshly prepared from 0.754 g (32.77 mmol) of sodium in 10 mL of
methanol and the reaction mixture was stirred at room temperature for 1
h. The mixture was evaporated to dryness, dissolved in 50 mL of toluene
and 4.87 g (25.21 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate was
added. The resulting solution was stirred under reflux for 12 h. The
cooled solution was evaporated to remove solvent. The mixture was
dissolved in dichloromethane, washed with a saturated aqueous solution of
ammonium chloride, saturated aqueous sodium chloride, dried over sodium
sulfate and evaporated to dryness. The residue was chromatographed on
silica gel eluting with a mixture of dichloromethane/methanol/aqueous
ammonia solution (29%) in the proportions 97/310.3 led to afford 3.2 g
(34%) of the desired compound as a white powder.

[0186]To a solution of 3.2 g (8.59 mmol) of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione dissolved in 24 mL of ethanol was added 2.09
mL (43 mmol) of hydrazine hydrate and the resulting mixture was stirred
under reflux for 2 hours. The mixture was filtered and the solid obtained
was triturated with dichloromethane for 24 h, filtered, and the resulting
filtrates were evaporated to dryness. The resulting residue was purified
on silica gel eluting with a mixture of dichloromethane/methanol in the
proportions 98/2 to 96/4 to give 1.37 g (66%) of the desired compound as
a brown powder.

[0191]Water was added and the mixture extracted with dichloromethane. The
extracts were washed with a saturated aqueous solution of ammonium
chloride, dried and evaporated. The residue was triturated with diethyl
ether and filtered to afford 0.105 g (84%) of the pure product as a
yellow powder.

[0195]To a solution of 0.080 g (0.33 mmol) of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
in 2 ml of toluene was added 0.045 g (0.33 mmol) of 2-methoxybenzaldehyde
and the resulting solution was refluxed for 3 h in a Dean-Stark
apparatus.

[0196]The resulting mixture was dried over sodium sulfate, filtered and
evaporated. The residue was dissolved in 2 mL of methanol, pH was
adjusted to 6 with acetic acid and 0.042 g (0.66 mmol) of sodium
cyanoborohydride was added. The resulting mixture was stirred at room
temperature for 1 h. The reaction mixture was concentrated, the residue
was dissolved in dichloromethane, washed with a saturated aqueous
solution of ammonium chloride, saturated aqueous solution of sodium
chloride, dried over sodium sulfate and evaporated. The base was
transformed into its hydrochloride salt to give 0.081 g of pure product.

[0200]To a solution of 0.07 g (0.29 mmol) of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
dissolved in 1 mL of dichloromethane at 10° C. was added 0.034 g
(0.29 mmol) of phenylisocyanate dissolved in 1 mL at 10° C. The
resulting mixture was stirred at 10° C. for 30 min. The mixture
was stirred at room temperature for 1 h.

[0201]The reaction mixture was concentrated, and the residue was
chromatographed on silica gel eluting with a mixture of
dichloromethane/methanol/aqueous ammonia solution (29%) in the
proportions 90/10/1. The residue was triturated with diethyl ether and
filtered to afford 0.088 g (84%) of the pure product as a brown powder.

[0205]To a solution of 0.07 g (0.29 mmol) of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one
dissolved in 4 mL of tetrahydrofuran at 0° C. was added 29.2 μl
(0.29 mmol) of triethylamine and 50 μl (0.32 mmol) of
phenylchloroformate. The resulting mixture was stirred at 0° C.
for 45 min and warmed at room temperature for 16 h.

[0206]A saturated aqueous solution of ammonium chloride was added and the
reaction mixture extracted with ethyl acetate. The extracts were dried
and evaporated. The residue was triturated with diethyl ether and
filtered to afford 0.068 g (65%) of the pure product as a white powder.

[0210]By analogy with the method described in example 1 (step 1.3), using
ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the
method described in patent DE 2705582) in place of ethyl
3-(pyridin-4-yl)-3-oxopropionate, the compound was obtained as a white
powder.

[0214]By analogy with the method described in example 1 (step 1.4), using
(+/-) 2-(4-oxo-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimi-
din-9-yl)-1H-isoindole-1,3(2H)-dione in place of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.

[0218]By analogy with the method described in example 1 (step 1.5), using
(+/-) 9-amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimid-
in-4-one in place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0232]By analogy with the method described in example 1 (step 1.1), using
2-(2-Oxo-pyrrolidin-3-yl)-isoindole-1,3-dione (prepared by analogy to the
method described in (Heterocycles (1996), 42(2), 537-42, Enantiomer
(2001), 6(5), 275-279, Synthesis (1991), (5), 417-20)) in place of
3-phtalimidopiperidin-2-one, the compound was obtained as a white powder.

[0236]By analogy with the method described in example 1 (step 1.2), using
2-(2-methoxy-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione in place of
2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione,
the compound was obtained as a white powder.

[0240]By analogy with the method described in example 1 (step 1.3), using
ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the
method described in patent DE 2705582) in place of ethyl
3-(pyridin-4-yl)-3-oxopropionate and using
2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound
was obtained as a white powder.

[0244]By analogy with the method described in example 1 (step 1.4), using
2-(4-oxo-2-pyrimidin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl-
)-isoindole-1,3-dione in place of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.

[0248]By analogy with the method described in example 1 (step 1.5), using
8-Amino-2-pyrimidin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one in
place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0252]By analogy with the method described in example 1 (step 1.1), using
α-amino-ε-caprolactam monohydrochloride (commercially
available) in place of 3-phtalimidopiperidin-2-one, the compound was
obtained as a yellow oil.

[0255]By analogy with the method described in example 1 (step 1.2), using
2-(7-methoxy-3,4,5,6-tetrahydro-2H-azepin-6-yl)-1H-isoindole-1,3(2H)-dion-
e in place of
2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione,
the compound was obtained as a white powder.

[0259]By analogy with the method described in example 1 (step 1.3), using
ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the
method described in patent DE 2705582) in place of ethyl
3-(pyridin-4-yl)-3-oxopropionate and using
2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1),
the compound was obtained as a white powder.

[0263]By analogy with the method described in example 1 (step 1.4), using
(+/-) 2-(4-oxo-2-pyrimidin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azep-
in-10-yl)-1H-isoindole-1,3(2H)-dione in place of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.

[0267]By analogy with the method described in example 1 (step 1.5), using
(+/-) 10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin--
4(6H)-one in place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0280]By analogy with the method described in example 1 (step 1.2), using
2-(2-methoxy-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H-
)-dione in place of
2-(2-methoxy-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)-dione,
the compound was obtained as a white powder.

[0284]By analogy with the method described in example 1 (step 1.3), using
ethyl 3-(4-pyrimidinyl)-3-oxopropionate (prepared by analogy to the
method described in patent DE 2705582) in place of ethyl
3-(pyridin-4-yl)-3-oxopropionate and using
2-(2-amino-3-methyl-3,4,5,6-tetrahydropyridin-3-yl)-1H-isoindole-1,3(2H)--
dione hydrochloride (1:1) the compound was obtained as a white powder.

[0288]By analogy with the method described in example 1 (step 1.4), using
(+/-) 2-(1-methyl-5-oxo-7-pyrimidin-4-yl-1,2,3,4,4a,5-hexahydronaphthalen-
-1-yl)-1H-isoindole-1,3(2H)-dione in place of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.

[0292]By analogy with the method described in example 1 (step 1.5), using
(+/-) 5-amino-5-methyl-3-pyrimidin-4-yl-6,7,8,8a-tetrahydronaphthalen-1(5-
H)-one in place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0306]By analogy with the method described in example 1 (step 1.3), using
ethyl 3-(4-pyridinyl)-3-oxopropionate (prepared by analogy to the method
described in patent DE 2705582) and using
2-(2-amino-4,5-dihydro-3H-pyrrol-3-yl)-isoindole-1,3-dione, the compound
was obtained as a white powder.

[0310]By analogy with the method described in example 1 (step 1.4), using
2-(4-oxo-2-pyridin-4-yl-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin-8-yl)--
isoindole-1,3-dione in place of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.

[0314]By analogy with the method described in example 1 (step 1.5), using
8-Amino-2-pyridin-4-yl-7,8-dihydro-6H-pyrrolo[1,2-a]pyrimidin-4-one in
place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0318]By analogy with the method described in example 1 (step 1.3), using
ethyl 3-(pyridin-4-yl)-3-oxopropionate and using
2-(2-iminoazepan-3-yl)-1H-isoindole-1,3(2H)-dione hydrochloride (1:1),
the compound was obtained as a white powder.

[0322]By analogy with the method described in example 1 (step 1.4), using
(+/-) 2-(4-oxo-2-pyridin-4-yl-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepin-
-10-yl)-1H-isoindole-1,3(2H)-dione in place of (+/-)
2-(4-oxo-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl-
)-1H-isoindole-1,3(2H)-dione, the compound was obtained as a brown powder.

[0326]By analogy with the method described in example 1 (step 1.5), using
(+/-) 10-amino-2-pyridin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(-
6H)-one in place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0342]By analogy with the method described in example 1 (step 1.5), using
(-) 10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(-
6H)-one in place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0350]By analogy with the method described in example 1 (step 1.5), using
(+) 10-amino-2-pyrimidin-4-yl-7,8,9,10-tetrahydropyrimido[1,2-a]azepin-4(-
6H)-one in place of (+/-)
9-amino-2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one-
, the compound was obtained as a white powder.

[0354]A list of chemical structures and physical data for compounds of the
aforementioned formula (I), illustrating the present invention, is given
in table 1. The compounds have been prepared according to the methods of
the examples. In the table, m and o represent 1, Ph represents a phenyl
group, Me represent a methyl group, (Rot.) indicates the levorotatory or
dextrorotatory properties of the enantiomeric compound.

[0355]A list of chemical structures and physical data for compounds of the
aforementioned formula (I), illustrating the present invention, is given
in table 2. The compounds have been prepared according to the methods of
the examples. In the table, m represents 0 and o represents 1, (Rot.)
indicates the levorotatory or dextrorotatory properties of the
enantiomeric compound.

[0356]A list of chemical structures and physical data for compounds of the
aforementioned formula (I), illustrating the present invention, is given
in table 3. The compounds have been prepared according to the methods of
the examples. In the table 3, m represents 1 and o represents 2, (Rot.)
indicates the levorotatory or dextrorotatory properties of the
enantiomeric compound.

[0360]The reaction was stopped with 100 microliters of a solution made of
25 g polyphosphoric acid (85% P2O5), 126 ml 85%
H3PO4, H2O to 500 ml and then diluted to 1:100 before use.
An aliquot of the reaction mixture was then transferred to Whatman P81
cation exchange filters and rinsed with the solution described above.
Incorporated 33P radioactivity was determined by liquid scintillation
spectrometry.

[0361]The phosphorylated GS-1 peptide used in the example was the same one
as reported in Woodgett, J. R. (1989) Analytical Biochemistry 180,
237-241 and had the same sequence as reported therein, which reference is
incorporated herein by reference in its entirety.

[0362]The GSK3β inhibitory activity of the compounds of the present
invention are expressed in IC50, and as an illustration the range of
IC50's of the compounds in table 1 and table 2 are between 0.1
nanomolar to 3 micromolar concentrations. For example compound No. 33 of
table 1 shows an IC50 of 0.005 μM.

Formulation Example

1Tablets

[0363]The ingredients below were mixed by an ordinary method and
compressed by using a conventional apparatus.

[0366]The compounds of the present invention have GSK3β inhibitory
activity and are useful as an active ingredient of a medicament for
preventive and/or therapeutic treatment of diseases caused by abnormal
activity of GSK3β and more particularly of neurodegenerative
diseases.